Regulation of tumor promotion by RasGRP1

Summary

Principal Investigator: JOE WILLIAM RAMOS
Abstract: DESCRIPTION (provided by applicant): The mouse model of skin carcinogenesis has served to investigate the multistage nature of tumorigenesis and to identify novel oncogenes and tumor suppressor genes, as well as signaling pathways relevant in cancer. In the classic two-stage carcinogenesis model, Ras is activated by mutations induced by a carcinogen, and subsequent treatment with phorbol esters induces tumor promotion. However, the mechanisms that lead to tumor formation of cells initiated by Ras -and the participation of phorbol ester signaling pathways- are still poorly understood. Using the mouse skin model, we have identified RasGRP1 as a novel regulator of skin carcinogenesis. RasGRP1 links phorbol esters and Ras, since it is both, a high affinity phorbol ester receptor and a Ras activator. Using genetically modified mice we have shown that RasGRP1 participates in tumor initiation and progression in the two-stage carcinogenesis model through the biochemical activation of wild type Ras. Additionally, transgenic mice overexpressing RasGRP1 in the epidermis are prone to develop skin tumors spontaneously. Taken together, we hypothesize that RasGRP1 participates in carcinogenesis by mediating biochemical Ras activation and cooperating with oncogenic Ras in tumor formation. In this application, we propose to identify the mechanisms of cooperation between Ras and RasGRP1 during skin carcinogenesis, both in the absence and presence of Ras oncogenic mutations. In addition, we plan to extend our observation in mouse models to a human model using the 3-D organotypic culture of human skin. The specific aims are: (1) Determine the mechanism of tumorigenesis induced by RasGRP1 in the absence of Ras oncogenic mutations: following findings from our recent studies on wounding-induced tumors in the RasGRP1 transgenic mice, we will focus on the potential role of cytokines and EGFR ligands in activation of the RasGRP1-Ras axis in the skin;(2) Investigate the cooperation between RasGRP1 and oncogenic Ras in tumor progression in the skin: our hypothesis is that RasGRP1 activates wild type Ras isoforms, particularly N-Ras, and cooperates with oncogenic Ras in tumor progression;and (3) Elucidate the role of RasGRP1 in human keratinocyte homeostasis and transformation: we will use human in vitro models to validate and understand the functions of RasGRP1 in carcinogenesis. The significance of the studies is that the identification of RasGRP1 as a relevant target in Ras modulation in carcinogenesis can be used to develop new interventions for chemoprevention and/or cancer therapy. Moreover, the findings derived from this proposal should also contribute to advance our understanding of Ras signaling pathways beyond skin carcinogenesis, and may have applications to other systems where RasGRP1 is also expressed.
Funding Period: 2002-08-01 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes
    Matthew C Tuthill
    Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Room 315, 1236 Lauhala Street, Honolulu, HI 96813, USA
    Mol Cancer Ther 5:602-10. 2006
  2. pmc Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin
    Carolyn E Oki-Idouchi
    Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, HI 96813, USA
    Cancer Res 67:276-80. 2007
  3. pmc RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during multistage skin carcinogenesis
    Courtney T Luke
    Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813, USA
    Cancer Res 67:10190-7. 2007
  4. pmc RasGRP1 transgenic mice develop cutaneous squamous cell carcinomas in response to skin wounding: potential role of granulocyte colony-stimulating factor
    Federico R Diez
    Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA
    Am J Pathol 175:392-9. 2009
  5. pmc RasGRP1 is essential for ras activation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in epidermal keratinocytes
    Amrish Sharma
    Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA
    J Biol Chem 285:15724-30. 2010
  6. pmc Targeted deletion of RasGRP1 impairs skin tumorigenesis
    Amrish Sharma
    Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA
    Carcinogenesis 35:1084-91. 2014

Research Grants

Detail Information

Publications6

  1. pmc Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes
    Matthew C Tuthill
    Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Room 315, 1236 Lauhala Street, Honolulu, HI 96813, USA
    Mol Cancer Ther 5:602-10. 2006
    ..This result may have implications in the understanding of the antitumor effects of bryostatin 1 in the skin...
  2. pmc Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin
    Carolyn E Oki-Idouchi
    Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, 651 Ilalo Street, Honolulu, HI 96813, USA
    Cancer Res 67:276-80. 2007
    ..Taken together, these data are the first to provide evidence of a novel role for RasGRP1 in skin carcinogenesis and suggest that RasGRP1 may participate in tumorigenesis through modulation of Ras and autocrine pathways...
  3. pmc RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during multistage skin carcinogenesis
    Courtney T Luke
    Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813, USA
    Cancer Res 67:10190-7. 2007
    ..The present data suggests that RasGRP1 participates in skin carcinogenesis via biochemical activation of endogenous wild-type Ras and predisposes to malignant progression in cooperation with Ras oncogenic signals...
  4. pmc RasGRP1 transgenic mice develop cutaneous squamous cell carcinomas in response to skin wounding: potential role of granulocyte colony-stimulating factor
    Federico R Diez
    Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA
    Am J Pathol 175:392-9. 2009
    ....
  5. pmc RasGRP1 is essential for ras activation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in epidermal keratinocytes
    Amrish Sharma
    Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813, USA
    J Biol Chem 285:15724-30. 2010
    ..Given the role of TPA as a skin tumor promoter, our findings provide additional support for a role for RasGRP1 in skin carcinogenesis...
  6. pmc Targeted deletion of RasGRP1 impairs skin tumorigenesis
    Amrish Sharma
    Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA
    Carcinogenesis 35:1084-91. 2014
    ..Thus, we propose that RasGRP1 upregulates signaling from Ras and contributes to epidermal tumorigenesis by increasing the total dosage of active Ras. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Ras activation pathways in UVR-induced epidermal transformation
    JOE WILLIAM RAMOS; Fiscal Year: 2013
    ....
  3. Prostate carcinogenesis and PKC signaling
    MARCELO GABRIEL KAZANIETZ; Fiscal Year: 2013
    ..Our studies will therefore establish the potential role of PKCe in the etiology of prostate cancer and determine its potential significance as a therapeutic target. ..
  4. Signaling Modulators in Epidermal Carcinogenesis
    Todd W Ridky; Fiscal Year: 2013
    ....
  5. Significance of PELP1 in Breast Cancer Progression
    VALERIE ANN CORTEZ; Fiscal Year: 2013
    ..abstract_text> ..
  6. Crosstalk between Desmogleins and Canonical Hedgehog Signaling
    Donna Brennan; Fiscal Year: 2013
    ....
  7. TRP Ca2+ Channels in the Skin
    Haoxing Xu; Fiscal Year: 2013
    ..The goal of this proposed research is to lay the groundwork necessary to develop new therapeutic strategies for skin and other epithelial cancers. ..
  8. Signaling and Progression in Prostate Cancer
    Dan Theodorescu; Fiscal Year: 2013
    ..The long-term objective is to translate our understanding of prostate cancer progression mechanisms into the identification of new drug targets and pre-clinical models that recapitulate key aspects of the human disease. ..
  9. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  10. TARGETING ONCOGENE EXPRESSION TO SKIN IN TRANSGENIC MICE
    DENNIS ROOP; Fiscal Year: 2013
    ..This application proposes to test our novel hypothesis and use both our mouse models and DPTXM for human skin SCCs to test new therapeutic approaches for highly metastatic and aggressive skin SCCs. ..
  11. The role of Fyn and Srcasm in UVB-induced cutaneous neoplasia
    John T Seykora; Fiscal Year: 2013
    ..This work will also provide new candidate molecules that may improve topical therapies to treat AKs and cSCCs in patients. ..
  12. mTOR signaling in keratinocyte UVB response
    THERESA DIANE CARR; Fiscal Year: 2013
    ..mTOR is activated by sun exposure, and we believe mTOR contributes to the development of skin cancer. Our research will investigate mTOR as a possible target for the prevention of skin cancer. ..
  13. Apigenin restores TSP-1 expression in UVB-irradiated keratinocytes
    Jill C Pelling; Fiscal Year: 2013
    ..Identifying TSP-1 as a key target of apigenin and demonstrating its important role in chemoprevention by Api will provide a new target and rationale for improved treatment and prevention strategies for NMSC. ..
  14. Akt/mTOR Signaling in Energy Balance Modulation of Epithelial Carcinogenesis
    Stephen D Hursting; Fiscal Year: 2013
    ..Furthermore, the proposed studies will establish molecular mechanisms underlying the anticancer effects of CR, especially in the putative target cells (i.e., stem cells) for cancer development. ..
  15. Inhibiting Multiple Molecular Targets for Preventing Non-Melanoma Skin Cancer
    Mohammad Athar; Fiscal Year: 2013
    ..However, blocking either one of these molecular targets only partially blocks the development of NMSCs. This proposal attempts to block both of these molecular targets to abrogate the pathogenesis of the most common human cancer, NMSCs. ..
  16. Studying the initiation, progression and therapy of lung cancer in mouse models
    Martin McMahon; Fiscal Year: 2013
    ..The long-term goal of these experiments is the development of new and rationally designed strategies to more effectively treat lung cancer patients. ..
  17. Testing feasibility of artemisinin-based synthetic-lethal suppression of skin pho
    Georg T Wondrak; Fiscal Year: 2013
    ..Critical proof-of-principle data will be generated guiding the rational design of future mechanistic and preclinical studies that validate synthetic-lethal approaches for photochemoprevention. ..
  18. Role of SAG/RBX2 E3 Ubiquitin Ligase in Skin Carcinogenesis
    Yi Sun; Fiscal Year: 2013
    ....
  19. Role of Notch 1 signaling in esophageal carcinogenesis
    Kelly A Whelan; Fiscal Year: 2013
    ....
  20. P38 MAP KINASE SIGNALING IN SKIN
    Tatiana Efimova; Fiscal Year: 2013
    ..We are optimistic that the completion of the proposed studies will result in a better mechanistic understanding of the p384 role in epithelial carcinogenesis and its potential as an anti-cancer therapeutic target. ..
  21. Local Immunoregulation of Carcinogenesis
    Michael Girardi; Fiscal Year: 2013
    ....